Autonomic: Angiotensin-(1-7) Interactions in Hypertension

自主神经：高血压中血管紧张素 (1-7) 的相互作用

• 批准号: 8821988
• 负责人: Amy Christine Arnold
• 金额: $ 12.48万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-15 至 2016-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8821988
• 关键词: Acute; Address; Angiotensin II; Angiotensin II Receptor; Animal Model; Animals; Area; Autonomic nervous system; Autonomic nervous system disorders; Baroreflex; Biometry; Blood Pressure; Buffers; Cardiovascular system; Cause of Death; Cessation of life; Characteristics; Chronic; Clinical; Clinical Research; Complement; Data; Development; Disease; Educational process of instructing; Environment; Etiology; Euglycemic Clamping; Experimental Animal Model; Experimental Models; Extramural Activities; Failure; Feedback; Foundations; Fructose; Functional disorder; Generations; Glucose Clamp; Goals; Gold; Hepatic; Hormones; Human; Hypertension; Hypotension; Impairment; Infusion procedures; Insulin; Insulin Resistance; Intravenous; Journals; Laboratory Animal Production and Facilities; Link; Maintenance; Mentors; Mentorship; Metabolic; Metabolic syndrome; Metabolism; Methods; Modeling; Molecular; Neurosciences; Obesity; Outcome; Pathogenesis; Pathway interactions; Patients; Peptides; Peripheral; Pharmacology; Phase; Physicians; Physiological; Physiology; Plasma; Play; Population; Public Health; Rattus; Regulation; Renin-Angiotensin System; Research; Research Personnel; Residual state; Resources; Review Committee; Rodent; Role; Scientist; Services; Site; Stroke; Sympathetic Nervous System; Sympatholytics; Testing; Training; Universities; Vasodilation; angiotensin I (1-7); autonomic reflex; base; blood pressure reduction; cardiovascular disorder risk; career; career development; experience; feeding; heart disease risk; improved; in vivo; indexing; innovation; insulin sensitivity; neuromechanism; novel; patient population; programs; receptor; relating to nervous system; restraint; skills; targeted treatment; translational approach; treatment strategy

DESCRIPTION (provided by applicant): Project Summary Hypertension is a major public health problem associated with an increased risk for heart disease and stroke, leading causes of death worldwide. The majority of hypertensive subjects are now obese and many suffer from insulin resistance, but the molecular mechanisms linking cardiovascular and metabolic derangements in this disease are not fully understood. Increasing evidence suggests that the renin-angiotensin system (RAS), in particular overactivity of angiotensin (Ang) II, plays a pathogenic role in both hypertension and insulin resistance in part through modulation of the sympathetic nervous system. More recently, the vasodilatory peptide Ang-(1-7), which opposes Ang II actions, has been implicated in the pathogenesis of hypertension. While Ang-(1-7) lowers blood pressure and improve insulin action in rodents, the precise mechanisms involved in these effects are unclear. In addition, there are limited and contradictory studies in humans, and we propose that this is due to restraint of Ang-(1-7) cardiovascular actions by autonomic buffering mechanisms. We also propose that Ang-(1-7) improves cardiovascular and metabolic function by inhibiting the sympathetic nervous system. Indeed, our preliminary data suggests that plasma Ang-(1-7) levels are reduced in clinical populations with sympathetic activation. Furthermore, this Ang-(1-7) deficiency appears to interact with the sympathetic nervous system to contribute to hypertension and insulin resistance. Based on these findings, we will test the overall hypothesis that Ang-(1-7) lowers blood pressure and improves insulin sensitivity by opposing the sympathetic nervous system. We will use an innovative translational approach to test this hypothesis that combines integrative physiologic and pharmacologic methods in animal and human experimental models. In Aim 1, we will take advantage of the unique characteristics of central and peripheral autonomic failure patients to determine the contribution of sympatholytic and peripheral vasodilatory mechanisms, respectively, to Ang-(1-7) effects in the absence of baroreflex buffering. In Aim 2, we will examine Ang-(1-7) effects on peripheral and hepatic insulin sensitivity in fructose-fed rats, an established animal model of cardio-metabolic syndrome, and whether these effects involve sympathetic inhibition. Finally, in the independent phase, the PI will examine the importance of endogenous Ang-(1-7): sympathetic interactions to cardiovascular and metabolic function in fructose-fed rats. These collective studies will accomplish the PIs short-term research objective to examine interactions between the sympathetic nervous system and Ang-(1-7) for cardiovascular and metabolic regulation. The findings from these studies will improve our understanding of mechanistic pathways of the RAS, and have the potential to advance current concepts in the field of hypertension to improve targeted treatment approaches and outcomes in this disease. These studies logically build upon the PI's translational background in cardiovascular autonomic regulation, and will provide strong training and a research framework to establish an independent and novel area of research. The PI will acquire new expertise and skills in cutting edge methods to assess insulin action in rodents in the mentored phase of this application, to complement her integrative animal and clinical cardiovascular training and to provide the foundation to be an elite investigator with the capabilities to comprehensively investigate cardio-metabolic function. The clinical studies will be performed under the mentorship of Dr. Italo Biaggioni at Vanderbilt University, a world renowned physician scientist with expertise in neural-metabolic interactions, and in autonomic disorders including primary autonomic failure. The PI will receive training in hyperinsulinemic-euglycemic clamps under the co-mentor Dr. David Wasserman, an expert in metabolism with over 20 years of experience in these methods. The PI has also established an outstanding mentoring team with a proven track record of mentorship and scientific expertise in the RAS, experimental and clinical hypertension, autonomic neuroscience, and biostatistics. Thus, these studies will be conducted in the optimal scientific environment with input from highly experienced mentors, access to unique patient populations, state-of-the-art clinical research and animal facilities, and a wealth of institutional resources for career development. Finally, the PI will participate in extramural activities to enhance her progression into an independent investigator including continued service on national physiology, pharmacology and autonomic committees, reviewing for journals and participating in teaching and mentorship opportunities. Overall, this proposal will advance the PIs long-term research and career goals, to establish a translational independent research program focused on the neural mechanisms of hypertension.

描述（由申请人提供）：项目摘要高血压是与心脏病和中风的风险增加有关的主要公共卫生问题，这是全球死亡的主要原因。现在，大多数高血压受试者现在都是肥胖的，许多受试者患有胰岛素抵抗，但是在该疾病中关联心血管和代谢危险的分子机制尚未完全了解。越来越多的证据表明，肾素 - 血管紧张素系统（RAS），特别是血管紧张素（ANG）II的过度活动性，在高血压和胰岛素抵抗中起着致病的作用，部分通过调节交感神经系统。最近，反对ANG II作用的血管舒张肽Ang-（1-7）与高血压的发病机理有关。虽然Ang-（1-7）降低了血压并改善啮齿动物的胰岛素作用，但涉及这些作用的确切机制尚不清楚。此外，在人类中有有限和矛盾的研究，我们建议这是由于限制了通过自主性缓冲机制对Ang-（1-7）心血管作用的限制。我们还建议ANG-（1-7）通过抑制交感神经系统来改善心血管和代谢功能。实际上，我们的初步数据表明，在具有交感神经激活的临床种群中，血浆ANG-（1-7）水平降低。此外，这种ANG-（1-7）缺乏似乎与交感神经系统相互作用，有助于高血压和胰岛素抵抗。基于这些发现，我们将检验总体假设，即Ang-（1-7）通过反对交感神经系统来降低血压并提高胰岛素敏感性。我们将使用一种创新的翻译方法来检验这种假设，该假设结合了动物和人类实验模型中的综合生理和药理方法。在AIM 1中，我们将利用中央和周围自主性失败患者的独特特征，以确定分别在没有巴罗洛弗利弗莱克斯缓冲的情况下，分别确定交感神经和外周血管舒张机制对Ang-（1-7）效应的贡献。在AIM 2中，我们将检查Ang-（1-7）对果糖喂养大鼠外周和肝胰岛素敏感性的影响，果糖喂养的大鼠，一种已建立的心脏代谢综合征动物模型，以及这些作用是否涉及交感神经抑制。最后，在独立阶段，PI将检查内源性Ang-（1-7）的重要性：果糖喂养大鼠中对心血管和代谢功能的交感神经相互作用。这些集体研究将完成PIS短期研究目标，以检查心血管和代谢调节的交感神经系统与Ang-（1-7）之间的相互作用。这些研究的发现将提高我们对RA的机械途径的理解，并有可能提高高血压领域中当前的概念，以改善该疾病的靶向治疗方法和结果。 从逻辑上讲，这些研究基于PI在心血管自主法规中的翻译背景，并将提供强大的培训和研究框架，以建立独立和新颖的研究领域。 PI将获得新的专业知识和技能，以评估该应用程序的指导阶段中的啮齿动物的胰岛素作用，以补充她的综合动物和临床心血管训练，并为基金会提供了一名精英研究员 全面研究心脏代谢功能的功能。临床研究将在范德比尔特大学的Italo Biaggioni博士的指导下进行，这是一位世界知名的医师科学家，在神经代谢相互作用方面具有专业知识，并在包括原发性自主神经失败在内的自主疾病中进行了专业知识。 PI将接受同事戴维·瓦瑟曼（David Wasserman）博士的高胰岛素血糖夹的培训，他是代谢专家，在这些方法方面拥有超过20年的经验。 PI还建立了一个杰出的指导团队，具有RAS，实验和临床高血压，自主神经科学和生物统计学的指导和科学专业知识的良好记录。因此，这些研究将在最佳的科学环境中进行，经验丰富的导师的意见，获得独特的患者人群，最先进的临床研究和动物设施以及大量用于职业发展的机构资源。最后， PI将参加壁外活动，以增强她成为独立研究者的发展，包括继续为国家生理学，药理学和自主委员会提供服务，审查期刊并参与教学和指导机会。总体而言，该提案将促进PIS长期研究和职业目标，以建立一个针对高血压神经机制的转化独立研究计划。